Propofol causes vasodilation in vivo via TRPA1 ion channels: role of nitric oxide and BKCa channels.
Female; Male; Animals; Mice; Signal Transduction; TRPA1 Cation Channel; Arterial Pressure/drug effects; Vasodilator Agents/*pharmacology; Propofol/*pharmacology; Transient Receptor Potential Channels/genetics/*metabolism; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits/*physiology; Nitric Oxide/*physiology; TRPV Cation Channels/genetics/metabolism; Inbred C57BL; Knockout; Drug Evaluation; Preclinical
BACKGROUND: Transient receptor potential (TRP) ion channels of the A1 (TRPA1) and V1 (TRPV1) subtypes are key regulators of vasomotor tone. Propofol is an intravenous anesthetic known to cause vasorelaxation. Our objectives were to examine the extent to which TRPA1 and/or TRPV1 ion channels mediate propofol-induced depressor responses in vivo and to delineate the signaling pathway(s) involved. METHODS: Mice were subjected to surgery under 1.5-2.5% sevoflurane gas with supplemental oxygen. After a stable baseline in mean arterial pressure (MAP) was achieved propofol (2.5, 5.0, 10.0 mg/kg/min) was administered to assess the hemodynamic actions of the intravenous anesthetic. The effect of nitric oxide synthase (NOS) inhibition with L-NAME and/or calcium-gated K+ channel (BKCa) inhibition with Penetrim A (Pen A), alone and in combination, on propofol-induced decreases in mean arterial pressure were assessed in control C57Bl/6J, TRPA1-/-, TRPV1-/- and double-knockout mice (TRPAV-/-). RESULTS: Propofol decreased MAP in control mice and this effect was markedly attenuated in
Sinha Sayantani; Sinharoy Pritam; Bratz Ian N; Damron Derek S
PloS one
2015
1905-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1371/journal.pone.0122189" target="_blank" rel="noreferrer noopener">10.1371/journal.pone.0122189</a>
Overexpressing superoxide dismutase 2 induces a supernormal cardiac function by enhancing redox-dependent mitochondrial function and metabolic dilation.
Adenosine Triphosphate/biosynthesis; Animals; Arterial Pressure/drug effects; Bioenergetics; Blood Flow Velocity/drug effects; Cardiac function; Cardiac/drug effects/*enzymology; Catalase/pharmacology; Echocardiography; Female; Gene Expression; Heart/drug effects/*enzymology; Hydrogen Peroxide/*metabolism/pharmacology; Injections; Intravenous; Male; Metabolic dilation; Mice; Mitochondria; Myocardium/*enzymology; Myocytes; NG-Nitroarginine Methyl Ester/pharmacology; Oxidation-Reduction; Oxygen Consumption/drug effects; Redox regulation; Signal Transduction; Stroke Volume/drug effects; Superoxide dismutase 2 (SOD2); Superoxide Dismutase/*genetics/metabolism; Transgenic; Transgenic mice; Vasodilation/*drug effects
During heightened cardiac work, O2 consumption by the heart benefits energy production via mitochondria. However, some electrons leak from the respiratory chain and yield superoxide, which is rapidly metabolized into H2O2 by SOD2. To understand the systemic effects of the metabolic dilator, H2O2, we studied mice with cardiac-specific SOD2 overexpression (SOD2-tg), which increases the H2O2 produced by cardiac mitochondria. Contrast echocardiography was employed to evaluate cardiac function, indicating that SOD2-tg had a significantly greater ejection fraction and a lower mean arterial pressure (MAP) that was partially normalized by intravenous injection of catalase. Norepinephrine-mediated myocardial blood flow (MBF) was significantly enhanced in SOD2-tg mice. Coupling of MBF to the double product (Heart RatexMAP) was increased in SOD2-tg mice, indicating that the metabolic dilator, "spilled" over, inducing systemic vasodilation. The hypothesis that SOD2 overexpression effectively enhances mitochondrial function was further evaluated. Mitochondria of SOD2-tg mice had a decreased state 3 oxygen consumption rate, but maintained the same ATP production flux under the basal and L-NAME treatment conditions, indicating a higher bioenergetic efficiency. SOD2-tg mitochondria produced less superoxide, and had lower redox activity in converting cyclic hydroxylamine to stable nitroxide, and a lower GSSG concentration. EPR analysis of the isolated mitochondria showed a significant decrease in semiquinones at the SOD2-tg Qi site. These results support a more reductive physiological setting in the SOD2-tg murine heart. Cardiac mitochondria exhibited no significant differences in the respiratory control index between WT and SOD2-tg. We conclude that SOD2 overexpression in myocytes enhances mitochondrial function and metabolic vasodilation, leading to a phenotype of supernormal cardiac function.
Kang Patrick T; Chen Chwen-Lih; Ohanyan Vahagn; Luther Daniel J; Meszaros J Gary; Chilian William M; Chen Yeong-Renn
Journal of molecular and cellular cardiology
2015
2015-11
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.yjmcc.2015.09.001" target="_blank" rel="noreferrer noopener">10.1016/j.yjmcc.2015.09.001</a>